title: Normal mucus formation requires cAMP-dependent HCO3- secretion and Ca2+-mediated mucin exocytosis.
abstract: Evidence from the pathology in cystic fibrosis (CF) and recent results in vitro indicate that HCO3- is required for gel-forming mucins to form the mucus that protects epithelial surfaces. Mucus formation and release is a complex process that begins with an initial intracellular phase of synthesis, packaging and apical granule exocytosis that is followed by an extracellular phase of mucin swelling, transport and discharge into a lumen. Exactly where HCO3- becomes crucial in these processes is unknown, but we observed that in the presence of HCO3-, stimulating dissected segments of native mouse intestine with 5-hydroxytryptamine (5-HT) and prostaglandin E2 (PGE2) induced goblet cell exocytosis followed by normal mucin discharge in wild-type (WT) intestines. CF intestines that inherently lack cystic fibrosis transmembrane conductance regulator (CFTR)-dependent HCO3- secretion also demonstrated apparently normal goblet cell exocytosis, but in contrast, this was not followed by similar mucin discharge. Moreover, we found that even in the presence of HCO3-, when WT intestines were stimulated only with a Ca2+-mediated agonist (carbachol), exocytosis was followed by poor discharge as with CF intestines. However, when the Ca2+-mediated agonist was combined with a cAMP-mediated agonist (isoproterenol (isoprenaline) or vasoactive intestinal peptide) in the presence of HCO3- both normal exocytosis and normal discharge was observed. These results indicate that normal mucus formation requires concurrent activation of a Ca2+-mediated exocytosis of mucin granules and an independent cAMP-mediated, CFTR-dependent, HCO3- secretion that appears to mainly enhance the extracellular phases of mucus excretion.
authors.affiliation: N. Yang: Division of Respiratory Medicine, Department of Pediatrics, University of California School of Medicine, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0830, USA. jey010@ucsd.edu.
authors.forename: Ning
authors.initials: N
authors.lastname: Yang
authors.forename: Mary Abigail S
authors.initials: MA
authors.lastname: Garcia
authors.forename: Paul M
authors.initials: PM
authors.lastname: Quinton
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D005089:Exocytosis; D020397:Goblet Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018181:Mice, Inbred CFTR; D009077:Mucins / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology
chemical_list: D001639:Bicarbonates; D009077:Mucins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012701:Serotonin; D000242:Cyclic AMP; D015232:Dinoprostone; D002118:Calcium